Airway inflammation, airway remodeling, colonization with microorganisms, and parenchymal destruction are hallmarks of chronic obstructive pulmonary disease (COPD). In addition to cigarette smoking, infectious pathogens likely contribute to the decline in pulmonary function in COPD patients. The inflammatory process in patients with COPD displays a distinct pattern of inflammatory mediators and immune cells that are involved that are similar to the pattern seen in response to Pneumocystis jiroveci (PC). Evidence has now emerged on the importance of macrophage phenotype in COPD patients. Macrophages account for the majority of inflammatory cells recovered from bronchoalveolar lavage from COPD patients and are localized to sites of alveolar destruction. Further, the IL-4/IL-13 alternatively activated macrophage phenotype (AAM) has been implicated in several chronic lung diseases. We propose in this study to evaluate the relationship between the AAM and PC in lungs of COPD patients in the Lung Tissue Research Consortium. In 3 Aims we will 1) correlate PC colonization with the presence of AAMs in lung tissue samples, 2) determine through immunohistochemistry how the presence of PC correlates to the precise localization of macrophage phenotype and fibrosis, and 3) determine how PC burden and AAMs correlate to clinical outcome measurements. This project will investigate a novel mechanism of pathogenesis which may provide targets for potential future therapeutic interventions for patients with COPD. PUBLIC HEALTH RELEVANCE: Project Narrative Chronic obstructive pulmonary disease (COPD) affects 24 million Americans and causes chronic, life- threatening lung disease. It has recently been described that Pneumocystis jiroveci (PC) infection may be an important factor in the progression of the disease. This project will investigate the hypothesis that PC infection worsens pulmonary fibrosis development in patients with COPD through induction of alternative macrophage activation. We have demonstrated in mouse models that PC polarizes the macrophage response toward this pro-fibrotic phenotype. Establishing a correlation between PC infection and alternative macrophage activation will lead to the identification of therapeutic interventions that possibly will slow the development of pulmonary fibrosis and functional decline in these patients. (End of Abstract)